U.S. patent application number 13/445614 was filed with the patent office on 2012-10-18 for prodrugs of inhibitors of plasma kallikrein.
This patent application is currently assigned to Activesite Pharmaceuticals, Inc.. Invention is credited to Tamie Jo Chilcote, Sriram Narasimhan, Sukanto SINHA, Joghee Raju Suresh.
Application Number | 20120264798 13/445614 |
Document ID | / |
Family ID | 46168613 |
Filed Date | 2012-10-18 |
United States Patent
Application |
20120264798 |
Kind Code |
A1 |
SINHA; Sukanto ; et
al. |
October 18, 2012 |
PRODRUGS OF INHIBITORS OF PLASMA KALLIKREIN
Abstract
This invention provides new pharmaceutically useful compounds
that are prodrugs of inhibitors of plasma kallikrein and methods
and compositions for preventing or treating plasma kallikrein
dependent diseases or conditions, such as diabetic macular edema or
hemorrhagic stroke, by administering prodrugs of the formula:
##STR00001##
Inventors: |
SINHA; Sukanto; (San
Francisco, CA) ; Chilcote; Tamie Jo; (San Francisco,
CA) ; Suresh; Joghee Raju; (Bangalore, IN) ;
Narasimhan; Sriram; (Bangalore, IN) |
Assignee: |
Activesite Pharmaceuticals,
Inc.
San Francisco
CA
|
Family ID: |
46168613 |
Appl. No.: |
13/445614 |
Filed: |
April 12, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61517065 |
Apr 13, 2011 |
|
|
|
Current U.S.
Class: |
514/406 ;
514/423; 548/374.1; 548/537 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 11/06 20180101; C07D 231/14 20130101; A61P 25/28 20180101;
A61P 35/00 20180101; A61P 25/16 20180101; A61P 31/00 20180101; C07D
207/34 20130101; A61P 29/00 20180101; A61P 13/12 20180101; A61P
25/00 20180101; A61P 9/10 20180101; A61P 19/02 20180101; A61P 7/02
20180101; A61P 1/00 20180101 |
Class at
Publication: |
514/406 ;
548/537; 514/423; 548/374.1 |
International
Class: |
A61K 31/402 20060101
A61K031/402; C07D 231/14 20060101 C07D231/14; A61K 31/415 20060101
A61K031/415; A61P 9/10 20060101 A61P009/10; A61P 27/02 20060101
A61P027/02; A61P 13/12 20060101 A61P013/12; A61P 29/00 20060101
A61P029/00; A61P 25/00 20060101 A61P025/00; A61P 7/02 20060101
A61P007/02; A61P 31/00 20060101 A61P031/00; A61P 19/02 20060101
A61P019/02; A61P 1/00 20060101 A61P001/00; A61P 35/00 20060101
A61P035/00; A61P 11/06 20060101 A61P011/06; A61P 25/28 20060101
A61P025/28; A61P 25/16 20060101 A61P025/16; C07D 207/34 20060101
C07D207/34 |
Goverment Interests
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH OR DEVELOPMENT
[0002] This invention was made with United States Government
support under grant EY019629 awarded by the National Institutes of
Health to ActiveSite Pharmaceuticals, Inc. The Government has
certain rights to this invention.
Claims
1. A compound having the formula: ##STR00012## wherein Ar is an
aromatic ring selected from the group consisting of benzene,
pyridine and pyrimidine; m is an integer from 0-5; each R.sup.a is
independently selected from the group consisting of cycloalkyl,
haloalkyl, halogen, --OH, --OR.sup.1, --OSi(R.sup.1).sub.3,
--OC(O)O--R.sup.1, --OC(O)R.sup.1, --OC(O)NHR.sup.1,
--OC(O)N(R.sup.1).sub.2, --SH, --SR.sup.1, --S(O)R.sup.1,
--S(O).sub.2R.sup.1, --SO.sub.2NH.sub.2, --S(O).sub.2NHR.sup.1,
--S(O).sub.2N(R.sup.1).sub.2, --NHS(O).sub.2R.sup.1,
--NR.sup.1S(O).sub.2R.sup.1, --C(O)NH.sub.2, --C(O)NHR.sup.1,
--C(O)N(R.sup.1).sub.2, --C(O)R.sup.1, --C(O)H, --C(.dbd.S)R.sup.1,
--NHC(O)R.sup.1, --NR.sup.1C(O)R.sup.1, --NHC(O)NH.sub.2,
--NR.sup.1C(O)NH.sub.2, --NR.sup.1C(O)NHR.sup.1, --NHC(O)NHR.sup.1,
--NR.sup.1C(O)N(R.sup.1).sub.2, --NHC(O)N(R.sup.1).sub.2,
--CO.sub.2H, --CO.sub.2R.sup.1, --NHCO.sub.2R.sup.1,
--NR.sup.1CO.sub.2R .sup.1, --R.sup.1, --CN, --NO.sub.2,
--NH.sub.2, --NHR.sup.1, --N(R.sup.1).sub.2,
--NR.sup.1S(O)NH.sub.2, --NR.sup.1S(O).sub.2NHR.sup.1,
--NH.sub.2C(.dbd.NR.sup.1)NH.sub.2, --N.dbd.C(NH.sub.2)NH.sub.2,
--C(.dbd.NR.sup.1)NH.sub.2, --NH--OH, --NR.sup.1--OH,
--NR.sup.1--OR.sup.1, --N.dbd.C.dbd.O, --N.dbd.C.dbd.S,
--Si(R.sup.1).sub.3, --NH--NHR.sup.1, --NHC(O)N.HNH.sub.2, NO,
--N.dbd.C.dbd.NR.sup.1 and --S--CN, wherein each R.sup.1 is
independently alkyl or aryl; L is a linking group selected from the
group consisting of a bond, CH, and SO.sub.2; Q.sup.a, Q.sup.b, and
Q.sup.c are each members independently selected from the group
consisting of N, S, O and C(R.sup.q) wherein each R.sup.q is
independently selected from the group consisting of H, C.sub.1-8
alkyl, halogen and phenyl; Y is C or N; and the ring having Q ,
Q.sup.b, Q.sup.c and Y as ring vertices is a five-membered ring
having two double bonds; and pharmaceutically acceptable salts
thereof.
2. The compound of claim 1, wherein Q.sup.a is N; and Q.sup.b and
Q.sup.c are each selected from N, O and C(R.sup.q).
3. The compound of claim 1, wherein Q.sup.a is N and Q.sup.b and
Q.sup.c are each selected from N and C(R.sup.q).
4. The compound of claim 1, wherein Y is N, and Q.sup.a, Q.sup.b
and Q.sup.c are each independently C(R.sup.q), wherein each R.sup.q
is independently H or C.sub.1-8 alkyl.
5. The compound of claim 1, wherein Y is N, Q.sup.a and Q.sup.c are
C(R.sup.q) and Q.sup.b is CH.
6. The compound of claim 1, wherein Y is N and Q.sup.b is N.
7. The compound of claim 1, wherein L is a bond and Y is N.
8. The compound of claim 1, wherein L is a bond, Y is N, and Ar is
a benzene ring.
9. The compound of claim 1, wherein L is a bond.
10. The compound of claim 1, wherein L is --SO.sub.2--.
11. The compound of claim 1, wherein R.sup.a is H or
C.sub.1-C.sub.8 alkyl.
12. The compound of claim 1, wherein Q.sup.a is O; and Q.sup.b and
Q.sup.c are each selected from N, O and C(R.sup.q).
13. The compound of claim 1, wherein Q.sup.a is O; and Q.sup.b and
Q.sup.c are each selected from N and C(R.sup.q).
14. The compound of claim 1, having the formula: ##STR00013##
15. The compound of claim 14, wherein each R.sup.q is independently
selected from the group consisting of H and C .sub.1-C.sub.8 alkyl;
and L is a bond or --CH.sub.2--.
16. The compound of claim 14, wherein L is a bond, Ar is benzene
and R.sup.a is a halogen.
17. The compound of claim 14, wherein R.sup.a is --CF.sub.3 or
--CH.sub.2CF.sub.3
18. The compound of claim 1, having the formula: ##STR00014##
wherein Ar is an aromatic ring.
19. The compound of claim 18, wherein each R.sup.q is independently
selected from the group consisting of H, halogen and
C.sub.1-C.sub.8 alkyl.
20. The compound of claim 18, wherein L is selected from the group
consisting of a bond and --CH.sub.2--.
21. The compound of claim 18, wherein Ar is a benzene ring.
22. The compound of claim 18, wherein Ar is a benzene ring, m is 0,
each R.sup.q is H, and L is --CH.sub.2--.
23. The compound of claim 1, selected from the group consisting of:
(a)
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyllmethyl]-2,5-dime-
thyl-pyrrole-3-carboxamide; (b)
1-(4-chlorophenyl)-N-[[4-(N'-hydroxycarbarnimidoyl)phenyl]methyl]-2,5-dim-
ethyl-pyrrole-3-carboxamide; (c)
1-(4-methoxyphenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dim-
ethyl-pyrrole-3-carboxamide; (d) 1-benzyl-N- [[4-(N'-hydroxyc
arbamimi doyl)phenyl]methyl]pyrazole-4-carboxamide. (e)
N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dimethyl-1-(4-pyridylme-
thyl)pyrrole-3-carboxamide.
24. A compound of claim 23, wherein said compound is
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbarnirnidoyl)phenyl]methyl]-2,5-di-
methyl-pyrrole-3-carboxamide.
25. A compound of claim 23, wherein said compound is 1-benzyl-N-[[4
-(N'-hydroxycarbamimidoyl)phenyl]methyl]pyrazole-4-carboxamide.
26. A method of treating a disease or condition that can be treated
with a plasma kallikrein inhibitor, said method comprising
administering to a subject in need thereof a pharmaceutically
effective amount of a compound of claim 1.
27. A method of claim 26, wherein said disease or condition is
selected from the group consisting of ischemic stroke, hemorrhagic
stroke, hypertensive retinopathy, hypertensive nephropathy,
cerebrovascular edema, inflammation, pain, acute myocardial
infarction (MD, deep vein thrombosis (DVT), complications from
fibrinolytic treatment with tissue plasminogen activator or
streptokinase following stroke or MI, angioedema, sepsis,
arthritis, complications of cardiopulmonary bypass, capillary leak
syndrome, inflammatory bowel disease, diabetic retinopathy,
diabetic macular edema, diabetic nephropathy, diabetic neuropathy,
age-related macular degeneration, retinal vein occlusions, brain
edema, ischemia-reperfusion injury, angiogenesis (e.g., in cancer),
asthma, anaphylaxis, and cerebrovascular complications of
neurological conditions such as Alzheimer's Disease, Parkinson's
Disease, multiple sclerosis, CNS infections, and glioblastoma
multiforme.
28. A method of claim 27, wherein said disease or condition is
diabetic macular edema.
29. A composition comprising a pharmaceutically acceptable
excipient and a compound of claim 1.
30. A composition of claim 29, wherein said compound is selected
from the group consisting of: (a) 1-
4-fluorophenyl)-N-[[4-hydroxycarbamimidoyl)phenyl]methyl]-2
5-dimethyl-pyrrole-3-ccarboxamide; (b)
1-(4-chlorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide; (c)
1-4-methoxyphenyl)-N-[[4-N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dimet-
hyl-pyrrole-3-carboxamide; (d)
1-benzyl-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]pyrazole-4-carboxam-
ide. (e)
N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dimethyl-1-(4-p-
yridylmethyl)pyrrole-3-carboxamide.
31. A composition of claim 29, wherein said compound is a
1-benzyl-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]pyrazole-4-carboxam-
ide.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Ser.
No.61/517,065, filed Apr. 13, 2011, the contents of which are
incorporated herein by reference.
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] Plasma kallikrein (PK), a serine protease present in plasma
as the inactive zymogen precursor plasma prekallikrein (prePK), is
proteolytically activated by FXIIa. In a positive feedback loop, PK
proteloytically activates the zymogen FXII, leading to additional
FXIIa formation, further amplifying its own activation. FXIIa also
activates the zymogen FXI to active FXIa, which results in the
initiation of the intrinsic (contact) pathway of blood coagulation,
resulting in generation of thrombin, and cleavage of fibrinogen.
Importantly, PK cleaves high molecular weight kininogen (HMWK) to
generate bradykinin. Bradykinin is able to open the tight junctions
between endothelial cells lining blood vessels by activating its
receptors, B1 and B2, present on the endothelial cells' surface,
and thus allowing fluid and plasma protein to extravasate into
tissue, a condition known as increased vascular permeability.
Disruption of tight junctions of the blood-brain barrier, and
consequent leakage of plasma and proteins into the brain (edema)
have also been associated with neurodegenerative diseases, such as
Alzheimer's Disease, Parkinson's Disease, and multiple sclerosis
(MS), as well as with CNS infections and brain tumors. For example,
peritumoral brain edema results in poorer prognosis in patients
with glioblastoma multiforme (Schoenegger K, Oberndorfer S, Eur J
Neurol. 2009 July; 16(7):874-8). The increased vascular
permeability caused by bradykinin formation can result in the
accumulation of excess fluid (edema) in many tissues and organs in
various diseases, e.g., angioedema, cystoid macular edema, diabetic
macular edema, macular edema after retinal vein occlusion,
cerebrovascular edema following stroke or head trauma, and
capillary leak syndrome. For example, the PK inhibitor ASP-440
(known from WO 2008/016883, and U.S. Pat. No. 7,625,944) has been
shown to reduce angiotensin-II-induced retinal vascular
permeability, and elevated systolic blood pressure (Phipps, J. A.,
et al. (2009) Hypertension 53: 175-181). Elevated levels of PK in
the eyes of rodents results in increased fluorescein leakage, and
retinal edema, and ASP-440 inhibits plasma leakage into the retina
in diabetic animals (Clermont A. C., et al. (2011) Diabetes, 60:
1590-8). Activation of prePK and the contact system has also been
shown to cause anaphylaxis, e.g., in patients treated with
contaminated heparin (Kishimoto, T. K., et al. (2008) N. Engl. J
Med. 358: 2457-2467).
[0005] Despite the developing body of knowledge surrounding plasma
kallikrein-releated diseases, there remains a need for the
development of new therapeutic agents that are useful in the
treatment of those diseases. Surprisingly, the present invention
provides such compounds.
BRIEF SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a new compound
having the formula:
##STR00002##
wherein Ar is an aromatic ring selected from the group consisting
of benzene, pyridine and pyrimidine; the subscript m is an integer
of from 0 to 5; each R.sup.a is independently selected from the
group consisting of cycloalkyl, haloalkyl, halogen, --OH,
--OR.sup.1, --OSi(R.sup.1).sub.3, --OC(O)O--R.sup.1,
--OC(O)R.sup.1, --(O)NHR.sup.1, --OC(O)N(R.sup.1).sub.2, --SH,
--SR.sup.1, --S(O)R.sup.1, --S(O).sub.2R.sup.1, --SO.sub.2NH.sub.2,
--S(O).sub.2NHR.sup.1, --S(O).sub.2N(R.sup.1).sub.2,
--NHS(O).sub.2R.sup.1, --NR.sup.1S(O).sub.2R.sup.1, --C(O)NH.sub.2,
--C(O)NHR.sup.1, --C(O)N(R.sup.1).sub.2, --C(O)R.sup.1, --C(O)H,
--C(.dbd.S)R.sup.1, --NHC(O)R.sup.1, --NR.sup.1C(O)R.sup.1,
--NHC(O)NH.sub.2, --NR.sup.1C(O)NH.sub.2, --NR.sup.1C(O)NHR.sup.1,
--NHC(O)NHR.sup.1, --NR.sup.1C(O)N(R.sup.1).sub.2,
--NHC(O)N(R.sup.1).sub.2, --CO.sub.2H, --CO.sub.2R.sup.1,
--NHCO.sub.2R.sup.1, --NR.sup.1CO.sub.2R.sup.1, --R.sup.1, --CN,
--NO.sub.2, --NH.sub.2, --NHR.sup.1, --N(R.sup.1).sub.2,
--NR.sup.1S(O)NH.sub.2, --NR.sup.1S(O).sub.2NHR.sup.1,
--NH.sub.2C(.dbd.NR.sup.1)NH.sub.2, --N.dbd.C(NH.sub.2)NH.sub.2,
--C(.dbd.NR.sup.1)NH.sub.2, --NH--OH, --NR.sup.1--OH,
--NR.sup.1--OR.sup.1, --N.dbd.C.dbd.O, --N.dbd.C.dbd.S,
--Si(R.sup.1).sub.3, --NH--NHR.sup.1, --NHC(O)NHNH.sub.2, NO,
--N.dbd.C.dbd.NR.sup.1 and --SCN, wherein each R.sup.1 is
independently C.sub.1-8 alkyl; L is a linking group selected from
the group consisting of a bond, CH.sub.2 and SO.sub.2;
[0007] Q.sup.a, Q.sup.b, and Q.sup.c are each members independently
selected from the group consisting of N, S, O and C(R.sup.q)
wherein each R.sup.q is independently selected from the group
consisting of H, C.sub.1-8 alkyl and phenyl, and the ring having
Q.sup.a, Q.sup.b, Q.sup.c and Y as ring vertices is a five-membered
ring having two double bonds; Y is a member selected from the group
consisting of C and N;
[0008] The compounds of general formula I are prodrugs of the
plasma kallikrein inhibitor compounds of general formula II, which
are already known from WO 2008/016883, and U.S. Pat. No. 7,625,944.
Approaches to synthesize prodrugs of compounds that contain amidine
moieties are known in the art. However, compounds of general
formula I have never been previously described or taught by the
prior art, nor have their particular advantages as PK inhibitors in
vivo been described. Upon administration to a subject in need of
treatment with a plasma kallikrein inhibitor, the compounds
provided herein are converted in vivo into compounds of general
formula II, and therefore have valuable properties as
pharmaceutical agents.
##STR00003##
[0009] The symbols Q.sub.a, Q.sub.b, Q.sub.c, Y, L, Ar, R.sup.a and
m in general formula II have the same meaning as in general formula
I.
[0010] The following are mentioned as examples of particularly
preferred compounds of general formula I: [0011] (a)
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide; [0012] (b)
1-(4-chlorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide; [0013] (c)
1-(4-methoxyphenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenylimethyl]-2,5-dim-
ethyl-pyrrole-3-carboxamide [0014] (d)
1-benzyl-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]pyrazole-4-carboxam-
ide. [0015] (e)
N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dimethyl-1-(4-pyridylme-
thyl)pyrrole-3-carboxamide
[0016] In another aspect, the present invention provides compounds
having the foimula:
##STR00004##
wherein the subscript m is an integer of from 0 to 5; the subscript
n is an integer of from 0 to 4; the subscript q is an integer of
from 0 to 1; L is a linking group selected from the group
consisting of a bond, CH.sub.2 and SO.sub.2; each of R.sup.b and
R.sup.e is independently selected from the group consisting of
cycloalkyl, haloalkyl, halogen, --OH, --OR.sup.2,
--OSi(R.sup.2).sub.3, --OC(O)O--R.sup.2, --OC(O)R.sup.2,
--OC(O)NHR.sup.2, --OC(O)N(R.sup.2).sub.2, --SH, --SR.sup.2,
--S(O)R.sup.2, --S(O).sub.2R.sup.2, --SO.sub.2NH.sub.2,
--S(O).sub.2NHR.sup.2, --S(O).sub.2N(R.sub.2).sub.2,
--NHS(O).sub.2R.sup.2, --NR.sup.2S(O).sub.2R.sup.2, --C(O)NH.sub.2,
--C(O)NHR.sup.2, --C(O)N(R.sup.2).sub.2, --C(O)R.sup.2, --C(O)H,
--C(.dbd.S)R.sup.2, --NHC(O)R.sup.2, --NR.sup.2C(O)R.sup.2,
--NHC(O)NH.sub.2, --NR.sup.2C(O)NH.sub.2, --NR.sup.2C(O)NHR.sup.2,
--NHC(O)NHR.sup.2, --NR.sup.2C(O)N(R.sup.2).sub.2,
--NHC(O)N(R.sup.2).sub.2, --CO.sub.2H, --CO.sub.2R.sup.2,
--NHCO.sub.2R.sup.2, --NR.sup.2CO.sub.2R.sup.2, --R.sup.2, --CN,
--NO.sub.2, --NH.sub.2, --NHR.sup.2, --N(R.sup.2).sub.2,
--NR.sup.2S(O)NH.sub.2, --NR.sup.2S(O).sub.2NHR.sup.2,
--NH.sub.2C(.dbd.NR.sup.2)NH.sub.2, --N.dbd.C(NH.sub.2)NH.sub.2,
--C(.dbd.NR.sup.2)NH.sub.2, --NH--OH, --NR.sup.2--OH,
--NR.sup.2--OR.sup.2, --N.dbd.C.dbd.O, --N.dbd.C.dbd.S,
--Si(R.sup.2).sub.3, --NH--NHR.sup.2, --NHC(O)NHNH.sub.2, NO,
--N.dbd.C.dbd.NR.sup.2 and --S--CN, wherein each R.sup.2 is
independently C.sub.1-8 alkyl; when q is 0, Z is a member selected
from the group consisting of O, S and NR.sup.d wherein R.sup.d is H
or C.sub.1-C.sub.8 alkyl; when q is 1, Z is N;
[0017] The compounds of general formula III are prodrugs of the
plasma kallikrein inhibitor compounds of general formula IV (the
parent compounds are described in WO 2008/016883, and U.S. Pat. No.
7,625,944). However, compounds of general formula III have not been
previously described. Upon administration to a subject in need of
treatment with a plasma kallikrein inhibitor, the compounds of
formula III are converted in vivo into compounds of general foimula
IV, and therefore have valuable properties as pharmaceutical
agents.
##STR00005##
[0018] Here, the symbols R.sup.b, R.sup.c, L, Z, m, n and q in
general formula IV have the same meaning as in general formula
III.
[0019] The following are mentioned as examples of particularly
preferred compounds of general formula III: [0020] (a)
1-benzyl-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]indole-3-carboxamid-
e; [0021] (b)
1-(benzenesulfonyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]indole-3-
-carboxamide.
[0022] In yet another aspect, the present invention provides a
pharmaceutical composition. The composition includes a compound of
formula I or III, in combination with a pharmaceutically acceptable
excipient.
[0023] In a further aspect, the present invention provides a method
of treating conditions associated with diabetes and hypertension,
e.g., retinopathy, macular edema, nephropathy, neuropathy and
elevated blood pressure.
[0024] In another aspect, the present invention provides a method
of treating a clinical condition that is caused by or is aggravated
by excessive vascular permeability and consequent edema, e.g.,
ischemic and hemorrhagic stroke, diabetic macular edema, cystoid
macular edema, retinal vein occlusions, age-related macular
degeneration, head trauma, capillary leak syndrome, and
glioblastoma multiforme.
[0025] In still another aspect, the present invention provides a
method of treating a plasma kallikrein-related disorder or
condition in a subject in need thereof. The method includes
administering to the subject a compound of formula I or III.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 provides structures of selected compounds of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0027] Unless otherwise stated the following terms used in the
specification and claims have the meanings given below.
[0028] The term "alkyl", by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain hydrocarbon radical, having the number of carbon atoms
designated (i.e. C.sub.1-8 means one to eight carbons). Examples of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
and the like. For each of the definitions herein (e.g., alkyl,
alkoxy, alkylamino, alkylthio, alkylene, haloalkyl), when a prefix
is not included to indicate the number of main chain carbon atoms
in an alkyl portion, the radical or portion thereof will have 12 or
fewer main chain carbon atoms.
[0029] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an
alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with
those groups having 10 or fewer carbon atoms being preferred in the
present invention. A "lower alkyl" or "lower alkylene" is a shorter
chain alkyl or alkylene group, generally having four or fewer
carbon atoms.
[0030] The term "cycloalkyl" refers to hydrocarbon rings having the
indicated number of ring atoms (e.g., C.sub.3-6cycloalkyl) and
being fully saturated or having no more than one double bond
between ring vertices. One or two C atoms may optionally be
replaced by a carbonyl. "Cycloalkyl" is also meant to refer to
bicyclic and polycyclic hydrocarbon rings such as, for example,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. When a prefix is
not included to indicate the number of ring carbon atoms in a
cycloalkyl, the radical or portion thereof will have 8 or fewer
ring carbon atoms.
[0031] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
Additionally, for dialkylamino groups, the alkyl portions can be
the same or different and can also be combined to form a 3-7
membered ring with the nitrogen atom to which each is attached.
Accordingly, a group represented as --NR.sup.aR.sup.b is meant to
include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the
like.
[0032] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "C.sub.1-4 haloalkyl" is mean to include
trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,
3-bromopropyl, and the like.
[0033] The term "aryl" means a monovalent monocyclic, bicyclic or
polycyclic aromatic hydrocarbon radical of 5 to 14 ring atoms which
is unsubstituted or substituted independently with one to four
substituents, preferably one, two, or three substituents selected
from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, cyano, hydroxy,
alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino,
haloalkyl, haloalkoxy, heteroalkyl, COR (where R is hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl cut, phenyl or phenylalkyl,
aryl or arylalkyl), --(CR'R'').sub.n--COOR (where n is an integer
from 0 to 5, R' and R'' are independently hydrogen or alkyl, and R
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl cut, phenyl or
phenylalkyl aryl or arylalkyl) or
--(CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R.sup.a
and R.sup.b are, independently of each other, hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, aryl or
arylalkyl). More specifically the term aryl includes, but is not
limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the
substituted forms thereof. Similarly, the term "heteroaryl" refers
to those aryl groups wherein one to five heteroatoms or heteroatom
functional groups have replaced a ring carbon, while retaining
aromatic properties, e.g., pyridyl, quinolinyl, quinazolinyl,
thienyl, and the like. The heteroatoms are selected from N, O, and
S, wherein the nitrogen and sulfur atoms are optionally oxidized,
and the nitrogen atom(s) are optionally quaternized. A heteroaryl
group can be attached to the remainder of the molecule through a
heteroatom. Non-limiting examples of aryl groups include phenyl,
naphthyl and biphenyl, while non-limiting examples of heteroaryl
groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl,
triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,
phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl,
benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl,
isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,
thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,
benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,
isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,
imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. For
brevity, the term aryl, when used in combination with other
radicals (e.g., aryloxy, arylalkyl) is meant to include both aryl
groups and heteroaryl groups as described above.
[0034] Substituents for the aryl groups are varied and are
generally selected from: -halogen, --OR', --OC(O)R', --NR'R'',
--SR', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'', --C(O)R',
--OC(O)NR'R'', --NR''C(O)R', --NR''C(O).sub.2R',
--NR'--C(O)NR''R''', --NH--C(NH.sub.2).dbd.NH,
--NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'', --N.sub.3,
perfluoro(C.sub.1-C.sub.4)alkoxy, and
perfluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to
the total number of open valences on the aromatic ring system; and
where R', R'' and R''' are independently selected from hydrogen,
C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted
aryl)-C.sub.1-4 alkyl, and unsubstituted aryloxy-C.sub.1-4
alkyl.
[0035] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CH.sub.2).sub.q--U--, wherein T and U are
independently --NH--, --O--, --CH.sub.2-- or a single bond, and q
is an integer of from 0 to 2. Alternatively, two of the
substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CH.sub.2--, --O--, --NH--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 3. One of the single bonds of the new ring so foinied may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CH.sub.2).sub.s--W--(CH.sub.2).sub.t--, where s and t are
independently integers of from 0 to 3, and W is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituent R' in --NR'-- and --S(O).sub.2NR'-- is selected from
hydrogen or unsubstituted C.sub.1-6 alkyl.
[0036] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0037] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds which are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of salts derived from pharmaceutically-acceptable inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable
organic bases include salts of primary, secondary and tertiary
amines, including substituted amines, cyclic amines,
naturally-occuring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperadine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge, S. M., et al.,
"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977,
66, 1-19). Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition salts.
The term "pharmaceutically acceptable" is meant the carrier,
diluent or excipient must be compatible with the other ingredients
of the formulation and not deleterious to the recipient
thereof.
[0038] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0039] The term "subject" as used herein is meant to include
animals, such as mammals, including, but are not limited to,
primates (e.g. humans), cows, sheep, goats, horses, dogs, cats,
rabbits, rats, mice and the like.
II. General
[0040] The present invention relates to compounds and methods of
using the compounds and pharmaceutical compositions for the
prevention and treatment of plasma kallikrein-dependent diseases or
conditions. The diseases or conditions that can be treated using
the compounds of the present invention include, but are not limited
to, ischemic stroke, hemorrhagic stroke, hypertension and its
vascular complications (especially retinopathy and nephropathy),
cerebrovascular edema, pulmonary hypertension, inflammation, pain,
acute myocardial infarction (MI), deep vein thrombosis (DVT),
complications from fibrinolytic treatment (e.g., with tissue
plasminogen activator, streptokinase) following stroke or MI,
angina, angioedema, sepsis, arthritis, complications of
cardiopulmonary bypass, capillary leak syndrome, inflammatory bowel
disease, diabetes and its vascular complications (especially
retinopathy, diabetic macular edema, nephropathy and neuropathy),
age-related macular degeneration, retinal vein occlusions, brain
edema, ischemia-reperfusion injury, angiogenesis (e.g., in cancer),
asthma, anaphylaxis, and cerebrovascular complications of
neurological conditions (e.g., Alzheimer's Disease, Parkinson's
Disease, multiple sclerosis, CNS infections, and glioblastoma
multiforme).
III. Compounds
[0041] In one aspect, the present invention provides compounds
having the formula:
##STR00006##
[0042] Ar is an aromatic ring selected from the group consisting of
benzene, pyridine and pyrimidine. In one embodiment, Ar is benzene
or pyridine. The subscript m is an integer from 0 to 5. In one
embodiment, m is 0.
[0043] Each R.sup.a is independently selected from the group
consisting of cycloalkyl, haloalkyl, halogen, --OH, --OR.sup.1,
--OSi(R.sup.1).sub.3, --OC(O)O--R.sup.1, --OC(O)R.sup.1,
--OC(O)NHR.sup.1, --OC(O)N(R.sup.1).sub.2, --SH, --SR.sup.1,
--S(O)R.sup.1, --S(O).sub.2R.sup.1, --SO.sub.2NH.sub.2,
--S(O).sub.2NHR.sup.1, --S(O).sub.2N(R.sup.1).sub.2,
--NHS(O).sub.2R.sup.1, --NR.sup.1S(O).sub.2R.sup.1, --C(O)NH.sub.2,
--C(O)NHR.sup.1, --C(O)N(R.sup.1).sub.2, --C(O)R.sup.1, --C(O)H,
--C(.dbd.S)R.sup.1, --NHC(O)R.sup.1, --NR.sup.1C(O)R.sup.1,
--NHC(O)NH.sub.2, --NR.sup.1C(O)NH.sub.2, --NR.sup.1C(O)NHR.sup.1,
--NHC(O)NHR.sup.1, --NR.sup.1C(O)NR.sup.1).sub.2,
--NHC(O)N(R.sup.1).sub.2, --CO.sub.2H, --CO.sub.2R.sup.1,
--NHCO.sub.2R.sup.1, --NR.sup.1CO.sub.2R.sup.1, --R.sup.1, --13 CN,
--NO.sub.2, --NH.sub.2, --NHR.sup.1, --N(R.sup.1).sub.2,
--NR.sup.1S(O)NH.sub.2, --NR.sup.1S(O).sub.2NHR.sup.1,
--NH.sub.2C(.dbd.NR.sup.1)NH.sub.2, --N.dbd.C(NH.sub.2)NH.sub.2,
--C(.dbd.NR.sup.1)NH.sub.2, --NH--OH, --NR.sup.1--OH,
--NR.sup.1--OR.sup.1, --N.dbd.C.dbd.O, --N.dbd.C.dbd.S,
--Si(R.sup.1).sub.3, --NH--NHR.sup.1, --NHC(O)NHNH.sub.2, NO,
--N.dbd.C.dbd.NR.sup.1 and --S--CN, wherein each R.sup.1 is
independently alkyl. In one embodiment, R.sup.1 is C.sub.1-C.sub.8
alkyl. In another embodiment, R.sup.1 is unsubstituted aryl, such
as phenyl or pyridyl, or a substituted aryl, such as a substituted
phenyl or a substituted pyridyl.
[0044] In one embodiment, each R.sup.a is independently selected
from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8alkoxy, aryl, aryl(C.sub.1-C.sub.8 alkyl), halogen,
--NH.sub.2, --NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8
alkyl).sub.2,--CN, --C(.dbd.O)(C.sub.1-C.sub.8 alkyl),
--(C.dbd.O)NH.sub.2, --(C.dbd.O)NH(C.sub.1-C.sub.8 alkyl),
--C(.dbd.O)N(C.sub.1-C.sub.8 alkyl).sub.2, --OH, --COOH,
--COO(C.sub.1-C.sub.8 alkyl), --OCO(C.sub.1-C.sub.8 alkyl),
--O(C.dbd.O)O(C.sub.1-C.sub.8 alkyl)--NO.sub.2, --SH,
--S(C.sub.1-C.sub.8 alkyl), --NH(C.dbd.O)(C.sub.1-C.sub.8 alkyl),
--NH(C.dbd.O)O(C.sub.1-C.sub.8 alkyl),
--O(C.dbd.O)NH(C.sub.1-C.sub.8 alkyl), --SO.sub.2(C.sub.1-C.sub.8
alkyl), --NHSO.sub.2(C.sub.1-C.sub.8 alkyl) and
--SO.sub.2NH(C.sub.1-C.sub.8 alkyl). In another embodiment, each
R.sup.a is independently selected from the group consisting of
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, phenyl, phenyl
(C.sub.1-C.sub.8 alkyl), halogen, --CN, --NH.sub.2,
--NH(C.sub.1-C.sub.8 alkyl), --N(C.sub.1-C.sub.8 alkyl).sub.2,
--(C.dbd.O)CH.sub.3, --(C.dbd.O)NH.sub.2, --OH, --COOH,
--COO(C.sub.1-C.sub.8 alkyl), --OCO(C.sub.1-C.sub.8 alkyl),
--O(C.dbd.O)O(C.sub.1-C.sub.8 alkyl), --NO.sub.2, --SH,
--S(C.sub.1-C.sub.8 alkyl), and
--NH(C.dbd.O)(C.sub.1-C.sub.8alkyl). In yet another embodiment,
each R.sup.a is indepedently selected from the group consisting of
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, phenyl, phenyl
(C.sub.1-C.sub.8 alkyl), phenoxy, aryloxy, halogen, --CN,
--NH.sub.2, --NH-aryl, --(C.dbd.O)CH.sub.3, --(C.dbd.O)NH.sub.2,
--OH, --COOH, --COO(C.sub.1-C.sub.8 alkyl), --OCO(C.sub.1-C.sub.8
alkyl), --COO-aryl, --OC(O)-aryl, --O(C.dbd.O)O(C.sub.1-C.sub.8
alkyl)--NO.sub.2, --SH, --S(C.sub.1-C.sub.8 alkyl),
--NH(C.dbd.O)(C.sub.1-C.sub.8 alkyl) and the like. For example,
R.sup.a is halogen, such as Cl, Br or I.
[0045] L is a linking group selected from the group consisting of a
bond, CH.sub.2 and SO.sub.2.
[0046] The ring vertex labeled Y is C or N. The vertices labeled
Q.sup.a, Q.sup.b, and Q.sup.c are each members independently
selected from the group consisting of N, S, O and C(R.sup.q)
wherein each R.sup.q is independently selected from the group
consisting of H, C.sub.1-8 alkyl, halogen and phenyl, and the ring
having Q.sup.a, Q.sup.b, Q.sup.c and Y as ring vertices is a
five-membered ring having two double bonds.
[0047] In a first group of embodiments, Q.sup.a is N and Q.sup.b
and Q.sup.c are each selected from N, O and C(R.sup.q). In certain
instances, Q.sup.a is N and Q.sup.c and Q.sup.b are each
independently selected from N and C(R.sup.q). In certain other
instances, Q.sup.a is N and Q.sup.c and Q.sup.b are each selected
from C(R.sup.q) and O. In yet certain other instances, Q.sup.a is
N, Q.sup.c is a member selected from N and O, and Q.sup.b is the
other member selected from N and O.
[0048] In a second group of embodiments, Q.sup.a is O and Q.sup.b
and Q.sup.c are each selected from N, O and C(R.sup.q). In certain
instances, Q.sup.a is O and Q.sup.c and Q.sup.b are each
independently selected from N and C(R.sup.q).
[0049] In a third group of embodiments, Q.sup.a is C(R.sup.q) and
Q.sup.b and Q.sup.c are each selected from N, O and C(R.sup.q). In
certain instances, Q.sup.a is C(R.sup.q) and Q.sup.b and Q.sup.c
are each independently selected from N and O. In certain other
instances, Q.sup.a is C(R.sup.q) and Q.sup.b and Q.sup.c are each
independently selected from N and C(R.sup.q). In .sub.yet certain
other instances, Q.sup.a is C(R.sup.q) and Q.sup.b and Q.sup.c are
each independently selected from O and C(R.sup.q). In one
occurrence, Q.sup.a is C(R.sup.q), Q.sup.b is O and Q.sup.c is
(CR.sup.q).
[0050] In one embodiment, Y is C, Q.sup.a is S and Ar is selected
from phenyl or pyridyl. In another embodiment, Y is N, Q.sup.a,
Q.sup.b and Q.sup.c are each independently C(R.sup.q), wherein
R.sup.q is H or C.sub.1-8alkyl. In one instance, Y is N, Q.sup.a
and Q.sup.c are C(R.sup.q) and Q.sup.b is CH. In a preferred
embodiment, Y is N.
[0051] In one embodiment, L is a bond, Y is N. In another
embodiment, L is a bond, Y is N and Ar is a benzene ring. In yet
another embodiment, L is CH.sub.2 and Y is N. In still another
embodiment, L is a bond and Y is C. In a further embodiment, L is
SO.sub.2 and Y is N.
[0052] In a preferred embodiment, Q.sup.a, Q.sup.b and Q.sup.c are
each independently CR.sup.q. In another preferred embodiment, L is
a bond or CH.sub.2. In still another preferred embodiment, Ar is
benzene. In still another preferred embodiment, R.sup.a is --H and
C.sub.1-C.sub.8 alkyl.
[0053] In another embodiment, the compounds of formula I have a
subformula Ia:
##STR00007##
wherein R.sup.q and L are as defined above. In one instance, each
R.sup.q is independently --H or C.sub.1-8 alkyl and L is a bond or
--CH.sub.2--. In another instance, L is a bond and R.sup.a is a
halogen. For example, R.sup.a is --Cl, --F.
[0054] In one embodiment, the compounds of formula I have a
subformula Ib:
##STR00008##
wherein Ar is an aromatic ring. In one instance, each R.sup.q is
independently H, C.sub.1-8 alkyl or halogen. In another instance, L
is a bond or CH.sub.2. In yet another instance, Ar is benzene. In
still another instance, m is 0. In one occurrence, each R.sup.q is
H, L is CH.sub.2, Ar is benzene and m is 0. In another occurrence,
each R.sup.q is H, L is a bond, Ar is benzene and m is 0.
[0055] The following are mentioned as examples of particularly
preferred compounds of general formula I: [0056] (a)
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyllmethyl]-2,5-dime-
thyl-pyrrole-3-carboxamide; [0057] (b)
1-(4-chlorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide; [0058] (c)
1-(4-methoxyphenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dim-
ethyl-pyrrole-3-carboxamide; [0059] (d)
1-benzyl-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]pyrazole-4-carboxam-
ide; [0060] (e)
N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dimethyl-1-(4-pyridylme-
thyl)pyrrole-3-carboxamide.
[0061] Preparation of Compounds
[0062] Many methods of synthesizing the compounds of the present
invention are known in the art. One preferred method for
synthesizing compounds of general formula I is illustrated
graphically below, where 1 equivalent of the corresponding
carboxylic acid is reacted with 1 equivalent of
4-(aminomethyl)benzonitrile in the presence of 1.1 equivalents of
oxalyl chloride, 3 equivalents of triethylamine in dichloromethane
at room temperature for 3 h (step a).
##STR00009##
[0063] In step b, the product of the first reaction is reacted with
hydroxylamine hydrochloride (3 equivalents) in ethanol at
80.degree. C. for 3 h, and the final product obtained by solvent
removal.
[0064] In the reaction described above, any reactive groups present
on the compound of general formula I, such as hydroxyl, carboxy,
amino, alkylamino or imino group may be protected during the
reaction by conventional protecting groups well-known to skilled
artisans, which can be subsequently removed by well-known chemical
methods after the reaction is completed.
[0065] The preferred methods of synthesis of the compounds of the
present invention, as described above, have an additional advantage
in that such compounds (e.g., those of general formula I) may be
synthesized in fewer steps than the corresponding PK inhibitors
(e.g., those of general formula II), and thus provide industrial
utility in reducing the cost and complexity of manufacture of PK
inhibitor compounds for administration to a subject in need of
treatment for a plasma kallikrein-dependent disease or
condition.
V. Pharmaceutical Compositions
[0066] In addition to having compounds of formula I and III
provided above, the compositions for prevention and treatment of
plasma kallikrein-related diseases or conditions in humans and
animals typically contain a pharmaceutical carrier, excipient and
diluent.
[0067] The pharmaceutical compositions for the administration of
the compounds of this invention may conveniently be presented in
unit dosage form and may be prepared by any of the methods well
known in the art of pharmacy and drug delivery. All methods include
the step of bringing the active ingredient into association with
the carrier, which constitutes one or more accessory ingredients.
In general, the pharmaceutical compositions are prepared by
uniformly and intimately bringing the active ingredient into
association with a liquid carrier or a finely divided solid carrier
or both, and then, if necessary, shaping the product into the
desired formulation. In the pharmaceutical composition, the active
object compound is included in an amount sufficient to produce the
desired effect upon the process or condition of diseases.
[0068] The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions and self emulsifications
as described in U.S. Patent Application No. 2002-0012680, hard or
soft capsules, syrups, elixirs, solutions, buccal patch, oral gel,
chewing gum, chewable tablets, effervescent powder and effervescent
tablets. Compositions intended for oral use may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents, antioxidants and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients,
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as cellulose, silicon
dioxide, aluminum oxide, calcium carbonate, sodium carbonate,
glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, corn
starch, or alginic acid; binding agents, for example PVP,
cellulose, PEG, starch, gelatin or acacia, and lubricating agents,
for example magnesium stearate, stearic acid or talc. The tablets
may be uncoated or they may be coated, enterically or otherwise, by
known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated by the techniques described in U.S. Pat. Nos.
4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic
tablets for controlled release.
[0069] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil. Additionally, emulsions can be
prepared with a non-water miscible ingredient such as oils and
stabilized with surfactants such as mono-diglycerides, PEG esters
and the like.
[0070] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
oleagino-propylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0071] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example, arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0072] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0073] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0074] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and
surfactants.
[0075] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0076] The compounds of the present invention may also be
administered in the form of suppositories for rectal administration
of the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter and polyethylene glycols. Additionally, the
compounds can be administered via ocular delivery by means of
solutions or ointments. Still further, transdermal delivery of the
subject compounds can be accomplished by means of iontophoretic
patches and the like. For topical use, creams, ointments, jellies,
solutions or suspensions, etc., containing the compounds of the
present invention are employed. As used herein, topical application
is also meant to include the use of mouth washes and gargles, as
well as eye-drops for opthalmological use.
[0077] The compounds of the invention may be formulated for
depositing into a medical device, which may include any of variety
of conventional grafts, stents, including stent grafts, catheters,
balloons, baskets or other device that can be deployed or
permanently implanted within a body lumen. As a particular example,
it would be desirable to have devices and methods which can deliver
compounds of the invention to the region of a body which has been
treated by interventional technique.
[0078] In exemplary embodiment, the inhibitory agent of this
invention may be deposited within a medical device, such as a
stent, and delivered to the treatment site for treatment of a
portion of the body.
[0079] Stents have been used as delivery vehicles for therapeutic
agents (i.e., drugs). Intravascular stents are generally
permanently implanted in coronary or peripheral vessels. Stent
designs include those of U.S. Pat. No. 4,733,655 (Palmaz), U.S.
Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062
(Wiktor). Such designs include both metal and polymeric stents, as
well as self-expanding and balloon-expandable stents. Stents may
also used to deliver a drug at the site of contact with the
vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz) and
in International Patent Application Nos. WO 91/12779 (Medtronic,
Inc.) and WO 90/13332 (Cedars--Sanai Medical Center), U.S. Pat. No.
5,419,760 (Narciso, Jr.) and U.S. Pat. No. 5,429,634 (Narciso,
Jr.), for example. Stents have also been used to deliver viruses to
the wall of a lumen for gene delivery, as disclosed in U.S. patent
application Ser. No. 08/746,404, filed Nov. 8, 1996 (Donovan et
al.).
[0080] The term "deposited" means that the inhibitory agent is
coated, adsorbed, placed, or otherwise incorporated into the device
by methods known in the art. For example, the inhibitory agent may
be embedded and released from within ("matrix type") or surrounded
by and released through ("reservoir type") polymer materials that
coat or span the medical device. In the later example, the
inhibitory agent may be entrapped within the polymer materials or
coupled to the polymer materials using one or more the techniques
for generating such materials known in the art. In other
formulations, the inhibitory agent may be linked to the surface of
the medical device without the need for a coating by means of
detachable bonds and release with time, can be removed by active
mechanical or chemical processes, or are in a permanently
immobilized form that presents the inhibitory agent at the
implantation site.
[0081] In one embodiment, the inhibitory agent may be incorporated
with polymer compositions during the formation of biocompatible
coatings for medical devices, such as stents. The coatings produced
from these components are typically homogeneous and are useful for
coating a number of devices designed for implantation.
[0082] The polymer may be either a biostable or a bioabsorbable
polymer depending on the desired rate of release or the desired
degree of polymer stability, but a bioabsorbable polymer is
preferred for this embodiment since, unlike a biostable polymer, it
will not be present long after implantation to cause any adverse,
chronic local response. Bioabsorbable polymers that could be used
include, but are not limited to, poly(L-lactic acid),
polycaprolactone, polyglycolide (PGA),poly(lactide-co-glycolide)
(PLLA/PGA), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,
polyanhydride, poly(glycolic acid), poly(D-lactic acid),
poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA)
, poly (L-lactide) (PLLA), poly(glycolic acid-co-trimethylene
carbonate) (PGA/PTMC), polyethylene oxide (PEO), polydioxanone
(PDS), polyphosphoester, polyphosphoester urethane, poly(amino
acids), cyanoacrylates, poly(trimethylene carbonate),
poly(iminocarbonate), copoly(ether-esters) (e.g., PEO/PLA),
polyalkylene oxalates, polyphosphazenes and biomolecules such as
fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic
acid, polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates, cross linked or amphipathic block copolymers of
hydrogels, and other suitable bioabsorbable poplymers known in the
art. Also, biostable polymers with a relatively low chronic tissue
response such as polyurethanes, silicones, and polyesters could be
used and other polymers could also be used if they can be dissolved
and cured or polymerized on the medical device such as polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers; acrylic
polymers and copolymers, vinyl halide polymers and copolymers, such
as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such
as polyvinyl methyl ether; polyvinylidene halides, such as
polyvinylidene fluoride and polyvinylidene chloride;
polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as
polystyrene, polyvinyl esters, such as polyvinyl acetate;
copolymers of vinyl monomers with each other and olefins, such as
ethylene-methyl methacrylate copolymers, acrylonitrile-styrene
copolymers, ABS resins, and ethylene-vinyl acetate copolymers;
pyran copolymer; polyhydroxy-propyl-methacrylamide-phenol;
polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysine
substituted with palmitoyl residues; polyamides, such as Nylon 66
and polycaprolactam; alkyd resins, polycarbonates;
polyoxymethylenes; polyimides; polyethers; epoxy resins,
polyurethanes; rayon; rayon-triacetate; cellulose, cellulose
acetate, cellulose butyrate; cellulose acetate butyrate;
cellophane; cellulose nitrate; cellulose propionate; cellulose
ethers; and carboxymethyl cellulose.
[0083] Polymers and semipermeable polymer matrices may be formed
into shaped articles, such as valves, stents, tubing, prostheses
and the like.
[0084] In one embodiment of the invention, the inhibitory agent of
the invention is coupled to a polymer or semipermeable polymer
matrix that is formed as a stent or stent-graft device.
[0085] Typically, polymers are applied to the surface of an
implantable device by spin coating, dipping or spraying. Additional
methods known in the art can also be utilized for this purpose.
Methods of spraying include traditional methods as well as
microdeposition techniques with an inkjet type of dispenser.
Additionally, a polymer can be deposited on an implantable device
using photo-patterning to place the polymer on only specific
portions of the device. This coating of the device provides a
uniform layer around the device which allows for improved diffusion
of various analytes through the device coating.
[0086] In preferred embodiments of the invention, the inhibitory
agent is formulated for release from the polymer coating into the
environment in which the medical device is placed. Preferably, the
inhibitory agent is released in a controlled manner over an
extended time frame (e.g., months) using at least one of several
well-known techniques involving polymer carriers or layers to
control elution. Some of these techniques were previously described
in U.S. Patent Application 20040243225A1, the entire disclosure of
which is incorporated in its entirety.
[0087] Moreover, as described for example in U.S. Pat. No.
6,770,729, which is incorporated herein in its entirety, the
reagents and reaction conditions of the polymer compositions can be
manipulated so that the release of the inhibitory agent from the
polymer coating can be controlled. For example, the diffusion
coefficient of the one or more polymer coatings can be modulated to
control the release of the inhibitory agent from the polymer
coating. In a variation on this theme, the diffusion coefficient of
the one or more polymer coatings can be controlled to modulate the
ability of an analyte that is present in the environment in which
the medical device is placed (e.g. an analyte that facilitates the
breakdown or hydrolysis of some portion of the polymer) to access
one or more components within the polymer composition (and for
example, thereby modulate the release of the inhibitory agent from
the polymer coating). Yet another embodiment of the invention
includes a device having a plurality of polymer coatings, each
having a plurality of diffusion coefficients. In such embodiments
of the invention, the release of the inhibitory agent from the
polymer coating can be modulated by the plurality of polymer
coatings.
[0088] In yet another embodiment of the invention, the release of
the inhibitory agent from the polymer coating is controlled by
modulating one or more of the properties of the polymer
composition, such as the presence of one or more endogenous or
exogenous compounds, or alternatively, the pH of the polymer
composition. For example, certain polymer compositions can be
designed to release an inhibitory agent in response to a decrease
in the pH of the polymer composition. Alternatively, certain
polymer compositions can be designed to release the inhibitory
agent in response to the presence of hydrogen peroxide.
VI. PK-dependent Diseases or Conditions
[0089] Further to the introduction of PK-dependent diseases or
conditions provided in the Background of the Invention, the
importance of bradykinin in vasogenic edema is further illustrated
in hereditary angioedema, in which individuals have little or no
functional C1-Inhibitor, the major endogenous inhibitor of PK. High
levels of bradykinin are generated in these individuals resulting
in extravasation of fluid and protein from the plasma into soft
tissue, thus causing life-threatening edema.
[0090] For example, bradykinin and its receptors have been shown to
be involved in tumor angiogenesis (Ikeda, Y., et al. (2004) Cancer
Research 64: 5178-5185), pulmonary hypertension
(Taraseviciene-Stewart, L., et al. (2005) Peptides 26: 1292-1300),
and asthma (Barnes, P. J., (1992) Recent Progress on Kinins,
AAS38/III, Birkhauser Verlag Basel).
[0091] C1-Inhibitor is also known to be involved in the
pathogenesis of age-related macular degeneration (Ennis, S., et al.
(2008) Lancet 372: 1828-1834) and ischemia-reperfusion injury
following organ transplant or myocardial infarction (Inderbitzin,
D., et al. (2004) Eur. Surg. Res. 36: 142-147; Horstick, G., et al.
(2001) Circulation 104: 3125-3131).
[0092] For patients with angioedema conditions, a small polypeptide
PK inhibitor (DX-88, ecallantide) alleviates edema in patients with
HAE (Williams, A. et al. (2003) Transfus. Apher. Sci. 29: 255-258;
Schneider, L. et al. (2007) J Allergy Clin Immunol. 120(2):416-22;
Levy, J. H. et al. (2006) Expert Opin. Invest. Drugs 15:
1077-1090). Similarly, a bradykinin B2 receptor antagonist,
icatibant, is also effective in treating HAE (Bork, K. et al.
(2007) J. Allergy Clin. Immunol. 119: 1497-1503). In view of the
role of PK in generating bradykinin, inhibition of PK can inhibit
bradykinin production.
[0093] In related disorders, thrombogenesis results from
fibrinolytic treatment (e.g. tissue plasminogen activator,
streptokinase), and higher levels of PK are found in patients
undergoing fibrinolysis (Hoffmeister, H. M. et al. (1998) J.
Cardiovasc. Pharmacol. 31: 764-72). Plasmin-mediated activation of
the intrinsic pathway has been shown to occur in plasma and blood
and was markedly attenuated in plasma from individuals deficient in
any of the intrinsic pathway components (Ewald, G. A. et al. (1995)
Circulation 91: 28-36).
[0094] Individuals who have had an acute MI were found to have
elevated levels of activated PK and thrombin (Hoffmeister, H.M., et
al. (1998) Circulation 98: 2527-33).
[0095] DX-88 reduced brain edema, infarct volume and neurological
deficits in an animal model of ischemic stroke (Storini, C., et al.
(2006) J. Pharm. Exp. Ther. 318: 849-854). C1-INH reduced infarct
size in a mouse model of middle cerebral artery occlusion (De
Simoni, M. G., et al. (2004) Am. J. Pathol. 164: 1857-1863; Akita,
N., et al. (2003) Neurosurgery 52: 395-400). By way of correlation,
the PK inhibitor ASP-440 was shown to reduce infarction volume and
cerebrovascular edema in a rat model of ischemic stroke, and
expansion of intracerebral hemorrhage in a model of hemorrhagic
stroke (Methods for Treatment of Kallikrein-Related Disorders,
WIPO, PCT WO 2009/0971; Liu, J., et al, Nat Med. (2011)17: 206-10).
B2 receptor antagonists were found to reduce the infarct volume,
brain swelling and neutrophil accumulation and were neuroprotective
in an animal model of ischemic stroke (Zausinger, S., et al.,(2003)
Acta Neurochir. SuppL 86: 205-207; Lumenta, D. B., et al. (2006)
Brain Res. 1069: 227-234; Ding-Zhou, L., et al. (2003) Br. J.
Pharmacol. 139: 1539-1547).
[0096] Regarding complications associated with cardiopulmonary
bypass (CPB) surgery, it has been found that the contact system is
activated during CPB (Wachtfogel, Y. T. (1989) Blood 73: 468)
consequently resulting in up to a 20-fold increase in plasma
bradykinin (Cugno, M. et al. (2006) Chest 120: 1776-1782; and
Campbell, D. J. et al. (2001) Am. J. Physiol. Reg. Integr. Comp.
Physiol. 281: 1059-1070). Capillary leak syndrome associated with
CPB can be reduced using a PK inhibitor (Mojcik, C. F., Levy, J.
H., Ann Thorac Surg. 2001 February; 71(2):745-54).
[0097] PK inhibitors, P8720 and PKSI-527 have also been found to
reduce joint swelling in rat models of arthritis (see, De La
Cadena, R. A. et al. (1995) FASEB J 9: 446-452; Fujimori, Y. (1993)
Agents Action 39: 42-48). It has also been found that inflammation
in animal models of arthritis was accompanied by activation of the
contact system (Blais, C. Jr. et al. (1997) Arthritis Rheum. 40:
1327-1333).
[0098] The PK inhibitor P8720 has been found to reduce inflammation
in an acute and chronic rat model of inflammatory bowel disease,
IBD (Stadnicki, A. et al. (1998) FASEB J, 12(3):325-33; Stadnicki,
A. et al. (1996) Dig. Dis. Sci. 41: 912-920; De La Cadena, R. A.,
et al. (1995) FASEB J. 9: 446-452). The contact system is activated
during acute and chronic intestinal inflammation (Sartor, R. B. et
al. (1996) Gastroenterology 110: 1467-1481). It has been found that
a B2 receptor antagonist, an antibody to high molecular weight
kininogen or reduction in levels of kininogen reduced
clinicopathology in animal models of IBD (Sartor, R. B. et al.
(1996) Gastroenterology 110: 1467-1481; Arai, Y. et al. (1999) Dig.
Dis. Sci. 44: 845-851; Keith, J. C. et al. (2005) Arthritis Res.
Therapy 7: R769-R776).
[0099] Still further, H-D-Pro-Phe-Arg-CMK, an inhibitor of PK and
FXIIa, as well as C1-Inhibitor have been shown to reduce vascular
permeability in multiple organs and reduce lesions in LPS or
bacterial induced sepsis in animals (Liu, D. et al. (2005) Blood
105: 2350-2355; Persson, K. et al. (2000) J. Exp. Med. 192:
1415-1424). Clinical improvement was observed in sepsis patients
treated with C1-Inhibitor (Zeerleder, S. et al. (2003) Clin.
Diagnost. Lab. Immunol. 10: 529-535; Caliezi, C., et al. (2002)
Grit. Care Med. 30: 1722-8; and Marx, G. et al. (1999) Intensive
Care Med. 25: 1017-20). Fatal cases of septicemia are found to have
a higher degree of contact activation (Martinez-Brotons, F. et al.
(1987) Thromb. Haemost. 58: 709-713; Kalter, E. S. et al. (1985) J.
Infect. Dis. 151: 1019-1027).
[0100] It has also been found that prePK levels are higher in
diabetics, especially those with proliferative retinopathy, and
correlate with fructosamine levels (Gao, B.-B., et al. (2007)
Nature Med. 13: 181-188; Kedzierska, K. et al. (2005) Archives Med
Res. 36: 539-543). PrePK is also found to be elevated in diabetics
and is highest in those with a sensomotor neuropathy (Christie, M.
et al. (1984) Thromb. Haemostas. 52: 221-223). PK has been found to
mediate hyperglycemia-induced cerebral hematoma expansion (Liu et
al. (2011) Nat. Med. 17:206-210) in a model of hemorrhagic stroke,
and to mediate retinal vascular dysfunction and induce retinal
thickening in diabetic rats (Clermont et al. (2011) Diabetes, epub
ahead of print March 28) in a model of diabetic retinopathy. PrePK
levels are elevated in diabetics and are associated with increased
blood pressure, independently correlate with the albumin excretion
rate, and are elevated in diabetics with macroalbuminuria
suggesting prePK may be a marker for progressive nephropathy
(Jaffa, A. A. et al. (2003) Diabetes 52: 1215-1221). B1 receptor
antagonists have been found to decrease enhanced vascular
permeability and plasma leakage into various organs, including the
skin and retina, in rats with streptozotocin-induced diabetes
(Lawson, S. R. et al. (2005) Eur. J. Pharmacol. 514: 69-78; Lawson
S R, Gabra B H, et al (2005) Regul Pept. 124:221-4). B1 receptor
antagonists can also prevent streptozotocin-treated mice from
developing hyperglycemia and renal dysfunction (Zuccollo, A., et
al. (1996) Can. J Physiol. Pharmacol. 74: 586-589).
[0101] Therefore, diseases or conditions that can be treated using
the compounds of the present invention include, but are not limited
to, ischemic stroke, hemorrhagic stroke, hypertension and its
vascular complications (especially retinopathy and nephropathy),
cerebrovascular edema, pulmonary hypertension, inflammation, pain,
acute myocardial infarction (MI), deep vein thrombosis (DVT),
complications from fibrinolytic treatment (e.g., with tissue
plasminogen activator, streptokinase) following stroke or MI,
angina, angioedema, sepsis, arthritis, complications of
cardiopulmonary bypass, capillary leak syndrome, inflammatory bowel
disease, diabetes and its vascular complications (especially
retinopathy, diabetic macular edema, nephropathy and neuropathy),
age-related macular degeneration, retinal vein occlusions, brain
edema, ischemia-reperfusion injury, angiogenesis (e.g., in cancer),
asthma, anaphylaxis, and cerebrovascular complications of
neurological conditions (e.g., Alzheimer's Disease, Parkinson's
Disease, multiple sclerosis, CNS infections, and glioblastoma
multiforme).
[0102] Upon administration to a subject in need thereof, the
compounds of general formulae I and III of the present invention
will be converted in vivo into PK inhibitors, and therefore lead to
inhibition of both the intrinsic pathway of blood coagulation, as
well as the formation of bradykinin from high molecular weight
kininogen. In this regard, the compounds of the present invention
have many pharmaceutical advantages over other PK inhibitors
described in the art. One advantage is in that their administration
to a subject via most clinically useful routes, e.g., oral,
subcutaneous, topical (including opthalmological eye-drops),
intraocular injection, etc., will result in higher levels of PK
inhibitor compound in plasma or the disease-affected organ (e.g.,
the eye) when compared to administration of the corresponding PK
inhibitor compound (described in WO 2008/016883, and U.S. Pat. No.
7,625,944) at a similar dose. This can result in a greater extent
of inhibition of PK in vivo, and therefore a larger therapeutic
effect. Another advantage is that their administration via routes
such as subcutanedus, intramuscular or topical, will result in a
slower appearance of the PK inhibitor compound in plasma or the
disease-affected organ (e.g., the eye), thus effectively prolonging
the time-period over which therapeutically useful levels of
compound will be maintained in vivo. Thus, less frequent dosing
would be required to maintain therepeutic levels in a subject in
need of treatment with a PK inhibitor.
[0103] The following examples are provided to illustrate various
aspects of the present invention.
EXAMPLE 1
Synthesis of
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide
##STR00010##
[0105] 30 g of 1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic
acid was reacted with 1 equivalent of 4-(aminomethyl)benzonitrile,
in the presence of 1.1 equivalents of oxalyl chloride, 3
equivalents of triethylamine in dichloromethane at room temperature
for 3 h. The product was then reacted with hydroxylamine
hydrochloride (3 equivalents) in ethanol at 80.degree. C. for 3h.
The target compound (36 g) was obtained as a tan-colored powder
following solvent removal by evaporation. Purity assessed by HPLC
was 97.8%, and mass was verified by LC/MS/MS (predicted m+1=381.2,
obtained m+1=381.2). .sup.1H-NMR (DMSO): .delta. 1.93 (3H), 2.21
(3H), 4.39-4.40 (2H), 5.76 (2H), 6.42 (1H), 7.26-7.28 (2H),
7.35-7.40 (4H), 7.60-7.62 (2H), 8.22 (1H), 9.56 (1H).
EXAMPLE 2
Conversion of prodrug
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide in vivo into the active plasma
kallikrein inhibitor
N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimeth-
yl-pyrrole-3-carboxamide
[0106] Young male Sprague-Dawley rats were orally dosed at 25 mg/kg
with the prodrug
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide dissolved in PEG400. Blood was removed
at various time intervals via an arterial catheter into a citrated
collection tube, and plasma generated by centrifugation. The
concentration of the active plasma kallikrein inhibitor
N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-
-3-carboxamide in the plasma samples were determined using
LC/MS/MS. The appearance of the active compound in plasma (see
Table 1 below) demonstrated that the prodrug compound
1-(4-fluorophenyl)-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]-2,5-dime-
thyl-pyrrole-3-carboxamide was absorbed from the gastrointestinal
tract following oral dosing, and effectively converted in vivo into
the active compound
N-[(4-carbamimidoylphenypmethyl]-1-(4-fluorophenyl)-2,5-dimethyl-
-pyrrole-3-carboxamide.
TABLE-US-00001 TABLE 1 N-[(4-carbamimidoylphenyl)methyl]-1-
(4-fluorophenyl)-2,5-dimethyl-pyrrole-3 carboxamide plasma levels
Time, h (ng/mL, mean .+-. s.d.) 0.25 299 .+-. 128 0.5 380 .+-. 75 1
312 .+-. 102 2 168 .+-. 21 4 83 .+-. 15 8 43 .+-. 16 12 43 .+-.
27
EXAMPLE 3
Synthesis of
1-benzyl-N-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]pyrazole-4-carboxam-
ide
##STR00011##
[0108] 20.8 g of 1-benzylpyrazole-4-carboxylic acid was reacted
with 1 equivalent of 4-(aminomethypbenzonitrile, in the presence of
1.1 equivalents of oxalyl chloride, 3 equivalents of triethylamine
in dichloromethane at room temperature for 3 h. The product was
then reacted with hydroxylamine hydrochloride (3 equivalents) in
ethanol at 80.degree. C. for 3h. The target compound (17.5 g) was
obtained as a off-white powder following solvent removal by
evaporation. Purity assessed by HPLC was 98.7%, and mass was
verified by LC/MS/MS (predicted m+1=350.2, obtained m+1=350.2).
.sup.1H-NMR (DMSO): .delta. 4.39-4.40 (2H), 5.34 (2H), 5.76 (2H),
7.25-7.30 (4H), 7.34-7.36 (3H), 7.59-7.62 (2H), 7.91 (1H), 8.27
(1H), 8.63 (1H), 9.57 (1H).
* * * * *